ABSTRACT: This application in response to RFA-DA-19-002 proposes a phased plan that will fast track the IND development of a next-generation medication for opioid use disorders (OUD). The small-molecule compounds proposed for development are targeted to the nociceptin opioid receptor (NOP) and have shown promising efficacy in reducing oxycodone intake in nonhuman primates (rhesus monkeys) trained to self-administer oxycodone with efficacies similar to that of buprenorphine. But unlike buprenorphine, the NOP-targeted agonist lead compounds show no reinforcing effects by themselves, in monkeys. Also unlike buprenorphine and methadone, currently used for treating OUDs, NOP-targeted lead compounds do not produce physical dependence, tolerance, or respiratory depression, upon repeated administration. For the non-medical prescription opioid addiction, methadone and buprenorphine, both approved for illicit opioid (heroin) addiction treatment, are used. However, methadone, a mu opioid receptor (MOP) full agonist has significant abuse liability and causes withdrawal after chronic use, reliance on methadone clinics, and risk of drug overdose- induced respiratory depression. Buprenorphine (Bup), a MOP partial agonist and kappa opioid receptor (KOP) antagonist, produces limited respiratory depression; however, clinical studies indicate that it is less effective than methadone in reducing drug use, craving and relapse. Agonists targeted to the nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, modulate the pharmacology of MOP agonists and opioids, particularly in pain and reward circuitries. Our preliminary data shows that small-molecule NOP agonists reduce morphine-induced reward in rodents and this is further confirmed in our preliminary data in nonhuman primates, demonstrating promising anti-rewarding properties of a NOP/MOP partial agonist in decreasing oxycodone self-administration without producing dependence or respiratory depression. Together our data thus far suggests that the NOP agonists are a promising new approach to treat illicit and prescription opioid use disorders and may offer an alternative to buprenorphine use. In the UG3 phase of this project, we propose to conduct non-GLP ADME-tox and efficacy confirmation, and additional lead optimization if warranted, with the goal/milestone being the nomination of a `IND candidate' and backup candidates, for IND-enabling studies and an IND filing (in the UH3phase).